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J Biol Chem ; 285(50): 38781-7, 2010 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-20889506

RESUMO

CCR7 binds to its cognate ligand, CCL21, to mediate the migration of circulating naive T lymphocytes to the lymph nodes. T lymphocytes can bind to fibronectin, a constituent of lymph nodes, via their ß1 integrins, which is a primary mechanism of T lymphocyte migration; however, the signaling pathways involved are unclear. We report that rapid (within 2 min) and transient phosphorylation of ERK1/2 is required for T cell migration on fibronectin in response to CCL21. Conversely, prevention of ERK1/2 phosphorylation by inhibition of its kinase, MAPK/MEK, prevented T lymphocyte migration. Previous studies have suggested that phospholipase Cγ1 (PLCγ1) can mediate phosphorylation of ERK1/2, which is required for ß1 integrin activation. Paradoxically, we found that inhibition of PLCγ1 phosphorylation by the general PLC inhibitor U73122 was associated with a delayed and reduced phosphorylation of ERK1/2 and reduced migration of T lymphocytes on fibronectin. To further characterize the relationship between ERK1/2 and PLCγ1, we reduced PLCγ1 levels by 85% using shRNA and observed a reduced phosphorylation of ERK1/2 and a significant loss of CCR7-mediated migration of T lymphocytes on fibronectin. In addition, we found that inhibition of ERK1/2 phosphorylation by U0126 resulted in a decreased phosphorylation of PLCγ1, suggesting a feedback loop between ERK1/2 and PLCγ1. Overall, these results suggest that the CCR7 signaling pathway leading to T lymphocyte migration on fibronectin is a ß1 integrin-dependent pathway involving transient ERK1/2 phosphorylation, which is modulated by PLCγ1.


Assuntos
Quimiocina CCL21/metabolismo , Fibronectinas/metabolismo , Regulação Enzimológica da Expressão Gênica , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosfolipase C gama/metabolismo , Receptores CCR7/metabolismo , Linfócitos T/citologia , Animais , Movimento Celular , Quimiocinas/metabolismo , Quimiotaxia , Humanos , Integrina beta1/metabolismo , Camundongos , Fosforilação , Linfócitos T/metabolismo
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